Arthritis is the most common chronic disease in the world, and there are many different reasons leading to, or causing arthritis, and joint injuries. Currently, the main drugs for the treatment of rheumatoid arthritis include adalimumab (Humira) of America Abbott Laboratories, etanercept (Enbrel) jointly developed by Pfizer and Amgen, and infliximab (Remicade) of Janssen Pharmaceutical Company. These, drugs are currently the best-selling drugs in the pharmaceutical market, but it is worth noting that these best-selling drugs are only injectable drugs. Although MTX (methotrexate), which is commonly administered orally, has pronounced efficacy, its toxicity is also significantly higher.
Studies, have shown that signaling pathway disorders of multiple cytokines play an important role in the pathophysiological process of rheumatoid arthritis (RA). The inflammatory cascade mediated by a series of uncontrolled cytokines leads to RA-related multiple cells, including T cells, B cells, monocytes, macrophages and osteoclasts in the long-term activated state, thereby causing persistent inflammation and joint structural damage. The Janus kinase (JAK) signaling pathway can regulate the proinflammatory activity of RA-related cells, wherein JAK is a hub protein in signal transduction of the inflammatory cytokine network, and the level of JAK is significantly increased in synovial tissues of RA joints. At present, tofacitinib (CP-690550) developed by Pfizer is a JAK1 inhibitor. The results of a phase III clinical trial showed that the efficacy of Pfizer's tofacitinib is significantly better than methotrexate. In this trial, the researchers randomly assigned patients, and one group of patients was administered 5 mg/10 mg of tofacitinib as a single drug, and the other group of patients were administered 5 mg/10 mg of methotrexate. The results showed that the efficacy of tofacitinib in reducing the progression of internal structural damage to human was slightly better than methotrexate in the period of six months, and that it could effectively improve various symptoms of rheumatoid arthritis patients.
We proceed from the idea of developing JAK kinase inhibitors following the global trend of drugs in the same category. Based on the structure of tofacitinib, we developed a series of drugs having in vitro and in vivo activities, and high absorption, and successfully obtained a compound of formula (IV) as a JAK kinase inhibitor. With regard to the compound of formula (IV), its information was completely described in PCT patent application No. PCT/CN2012/086922 filed jointly by the applicant together with other applicant, the content of which is herein incorporated by reference in its entirety.

Considering the lower solubility of the compound of formula (IV), we studied its salt-forms for improved solubility and bioavailability. The researched salts included salts of citric acid, hydrochloric acid and sulfuric acid. Based on the solubility data and pharmacokinetic results from animal experiments of the resulting salts, we surprisingly found that a compound of formula (I) was desirable to become a preferred JAK kinase inhibitor, which has a significant importance to the research and development in the treatment of rheumatism and rheumatoid arthritis.